The Neuropharmacology Research Unit
The Laboratory for Neuropharmacological Research (NeuroLab), at Department of Health Sciences of the University “Magna Græcia” of Catanzaro, is a research environment in which interdisciplinary research team works together to combine a scientific synthesis for a pharmacological approach to brain degenerative disease such as Alzheimer’s disease (AD). Alzheimer's disease (AD) and Alzheimer-like disease are caracterized by cognitive decline and impairment in memory ability as consequence of dysfunctions in several neurotransmitter systems, with the most pronounced deficency in the central cholinergic trasmission. In this contest, clinical symptoms present in AD are mostly associated with progressive degeneration of basal cholinergic forebrain neurons and consequent deficency in the cholinergic transmission.
Our research group, in the beginning of the ‘90s, was busy to develop an experimental model of Alzheimer’s disease. An original model of AD disease was produced by a very selective damage of a part of the Nucleus Basalis of Meynert (NBM), the main cholinergic system in brain arising the neocortex. In fact, this neuronal network is involved in brain function such as attention and cognition. Following that, our group used this original animal model as integrative approaches to study new and original compounds as putative agents against the neurodegenerative disease. Several new substances are tested by this animal model of AD by electrophysiological tools (qualitative and quantitative analysis of EEG spectrum, EEG brain mapping) and study of cognition and memory by different behavioural tasks.
Ongoing Research
Work focuses on:
AIM 1- Synthesis and pharmacological screening of chemical systems for the CNS delivery of drugs able to increase cholinergic tone or characterized by antioxidant and antiamiloidogenic properties.
Our research group performed the synthesis and the pharmacological study of chemical delivery systems able to cross the BBB and release choline to the brain, inducing in suitable animal models positive behavioral and electroencephalographic effects the activity of these compounds was correlated to the activation of the cholinergic system due either to a competitive inhibition of acetyl cholinesterase and release of choline following to the hydrolysis.
AIM 2 - Pharmacological evaluation in vitro and in experimental models of Alzheimer's disease, of novel multipotent drugs simultaneously able to increase cholinergic tone, interact with neuronal nicotinic acetylcholine receptors and prevent Acetylcholinesterase-induced aggregation of amyloid peptide.
Identification and optimization of natural products isolated from marine organisms as potential dual and/or multi-ligands of acetylcholinesterase enzyme and of neural nicotinic receptors for the treatment of Alzheimer's disease, by an integrated computational-experimental approach.
Neurosurgery
1. Stereotaxic apparatus for neurosurgery (small animals) (1996)
2. Stereomicroscope
Electrophysiology
3. Electroencephalograph for digital quantitative EEG (qEEG) (2006)
Behavioural instruments
4. Used in evaluating attention, learning and memory (2000)
§ Object recognition test;
§ Passive avoidance ;
§ Shuttle box
§ T-maze;
§ Y maze;
§ Radial maze,
§ Morris water maze
5. Video tracking system designed to automate testing in behavioural experiments (2004)
6. EthoVision XT 6.0 (Noldus) Video tracking system (2011)
Attention, learning & memory
§ Computerised, digital EEGraphers
One the of most advanced electrophysiological tools available at present, important to verify the quality of brain damage and quantify the neocortical activity after disruption of central cholinergic system arising from NBM to frontal cortex. Important informations of brain activity are carried out analyzing the EEG spectra power from total and selected range of neocortical frequencies as well as digital brain mapping.
§ Behavioural tasks
Antidementia compounds are screened for short- and long-term memory effects using primary and specific memory screen:
o Primary memory screen:
- Object recognition: to evaluate working-episodic memory;
- Passive avoidance: to evaluate non spatial memory;
o Specific memory screening
- Spontaneous alternation in a T-maze: to evaluate working spatial memory;
- Morris water maze and Radial maze: to evaluate spatial memory.
To remember a harmful stimulus, discriminated avoidance learning, to measure some amnesic effects, vigilance, spatial discrimination test, working memory, reference memory, learning performance , learning strategy , spontaneous alternation behavior, spatial discrimination, spatial discrimination, working memory, reference memory, spontaneous alternation behaviour.
Research Funding
1 COFIN-MIUR 1997;
2 COFIN-MIUR 2001 “Synthesis and pharmacological screening of chemical systems for the CNS delivery of drugs able to increase cholinergic tone”.
3 COFIN-MIUR 2003 “Synthesis and pharmacological screening of chemical systems for the CNS delivery of drugs able to increase cholinergic tone”.
4 COFIN-MIUR 2005 “Synthesis and pharmacological screening of chemical systems for the CNS delivery of drugs able to increase cholinergic tone or characterized by antioxidant and antiamiloidogenic properties.”
5 CNR, Istituto di Scienze Neurologiche “Pharmacological evaluation of novel compounds able to increase cholinergic tone in brain in experimental model of Alzheimer’s disease”.
6 MIUR-ITALY PRIN 2015 “Top-down and bottom-up approach in the development of new bioactive chemical entities inspired on natural products scaffolds” (Project No. 2015MSCKCE_003).
7 Alzheimer’s Association Grant NIRG-14-321500.
8 University of Naples “Parthenope”, “Bando per la ricerca individuale”
Patents
1. Carelli V., Liberatore F., Scipione L., Cardellini M., Rotiroti D., Rispoli V. “Choline derivatives for the treatment of Alzheimer’s Disease”. European Patent EP 1 274 674, 08.03.2006, Bullettin 2006/10.
2. Carelli V., Liberatore F., Scipione L., Cardellini M., Rotiroti D., Rispoli V. Preparation of cholinyl pivalate salys for the treatment of Alzheimer and other dementia associated with central cholinergic deficit. PCT Int. Appl. Patente Number WO 2001081296, 2001.
3. V. Carelli, F. Liberatore, L. Scipione, D. Rotiroti, V. Rispoli, M. Cardellini. “Choline derivatives for the treatment of Alzheimer’s Disease”, European Patent EP 01925883.9-10-4- 2001. C.A. 135 (2001) 344212M.
4. V. Carelli, F. Liberatore, L. Scipione, D. Rotiroti, V. Rispoli, M. Cardellini. “Choline derivatives for the treatment of Alzheimer’s Disease”, patent IT MI2000A000898-21 4-(2000).
Most relevant papers published
§ Vitale RM, Rispoli V, Desiderio D, Sgammato R, Thellung S, Canale C, Vassalli M, Carbone M, Ciavatta ML, Mollo E, Felicità V, Arcone R, Gavagnin M, Masullo M, Florio T, Amodeo P. In silico identification and experimental validation of novel anti-Alzheimer's multitargeted ligands from marine source featuring a "2-amino-imidazole plus aromatic group" scaffold. ACS Chem Neurosci. 2018 Feb 23. doi: 10.1021/acschemneuro.7b00416. [Epub ahead of print] PubMed PMID: 29473731.
§ Rispoli V, Ragusa S, Nisticò R, Marra R, Russo E, Leo A, Felicitá V, Rotiroti D. Huperzine a restores cortico-hippocampal functional connectivity after bilateral AMPA lesion of the nucleus basalis of meynert. J Alzheimers Dis. 2013;35(4):833-46. doi: 10.3233/JAD-130278. PubMed PMID: 23515019.
§ Cuomo O, Rispoli V, Leo A, Politi GB, Vinciguerra A, di Renzo G, Cataldi M. The antiepileptic drug levetiracetam suppresses non-convulsive seizure activity and reduces ischemic brain damage in rats subjected to permanent middle cerebral artery occlusion. PLoS One. 2013 Nov 13;8(11):e80852. doi: 10.1371/journal.pone.0080852. eCollection 2013. PubMed PMID: 24236205; PubMed Central PMCID: PMC3827478.
§ Rispoli V. Neural Basis of Object Recognition. 2011. In Advances in Object Recognition System, Ioannis Kypraios Ed. InTech Open Access 2011.
§ Siciliano R, Barone E, Calabrese V, Rispoli V, Butterfield DA, Mancuso C. Experimental research on nitric oxide and the therapy of Alzheimer disease: a challenging bridge. CNS Neurol Disord Drug Targets. 2011 Nov;10(7):766-76. Review. PubMed PMID: 21999733.
§ Rispoli V., Marra R., Costa N., Rotiroti D., Tirassa P., Scipione L., De Vita D., Liberatore F., Carelli V. (2008). Choline pivaloyl ester enhances brain expression of both nerve growth factor and high-affinity receptor TrkA, and reverses memory and cognitive deficits, in rats with excitotoxic lesion nucleus basalis magnocellularis. Behavioural Brain Research, vol. 190; p. 22-32, ISSN: 0166-4328.
§ Carelli V., Liberatore F:, Scipione L., Rispoli V., Rotiroti D., Cardellini M. (2006). “Choline derivatives for the treatment of Alzheimer's Disease”. EP 1 274 674. Università di Catanzaro "Magna Graecia", Università di Roma "La Sapienza", Università degli Studi di Camerino.
§ Rispoli V., Marra R., Costa N., Scipione L., Rotiroti D., De Vita D., Liberatore F., Carelli V. (2006). Choline pivaloyl ester strengthened the benefit effects of Tacrine and Galantamine on electroencephalographic and cognitive performances in nucleus basalis magnocellularis-lesioned and aged rats. Pharmacology Biochemistry and Behavior, vol. 84; p. 453.-467, ISSN: 0091-3057.
§ Rispoli V., Rotiroti D., Carelli V., Liberatore F., Scipione L., Marra R., Tortorella S., Di Rienzo B. (2004). Electroencephalographic effects induced by choline pivaloyl esters in scopolamine treated or nucleus basalis magnocellularis lesioned rats. Pharmacology Biochemistry and Behavior, Vol.78, 667-673, ISSN: 0091-3057.
§ CARELLI V., LIBERATORE L., SCIPIONE L., RISPOLI V., ROTIROTI D., CARDELLINI M. (2001). “Choline derivatives for the treatment of Alzheimer's Disease”. EPC 2103-IT0100191 , 18/4/2001. Università di Catanzaro "Magna Graecia", Università di Roma "La Sapienza", Università degli Studi di Camerino.
§ CARELLI V., LIBERATORE L., SCIPIONE L., RISPOLI V., ROTIROTI D., CARDELLINI M. (2000). “Choline derivatives for the treatment of Alzheimer's Disease”. Filed It. Pat. MI2000A000898, 21/4/2000. Università di Catanzaro "Magna Graecia", Università di Roma "La Sapienza", Università degli Studi di Camerino.
§ Alcaro S., Scipione L., Ortuso F., Posca S., Rispoli V., Rotiroti D. (2002). Molecular modeling and enzymatic studies of the interaction of a choline analogue and acetylcholinesterase. Bioorganic & Medicinal Chemistry Letters. Vol 12/20, pp2899-2905, ISSN: 0960-894X.
§ Rispoli V., Rotiroti D., Carelli V., Liberatore F., Scipione L., Marra R., Giorgioni G., Di Stefano A. (2004). Choline pivaloyl-esters improve in rats cognitive and memory performances impaired by scopolamine treatment or lesions of the nucleus basalis of Meynert, Neuroscience Letters, Vol 356(3), 199-202, ISSN: 0304-3940.
§ Mollace V, Iannone M, Muscoli C, Palma E, Granato T, Rispoli V., Nistico R, Rotiroti D, Salvemini D. (2003). The role of oxidative stress in paraquat-induced neurotoxicity in rats: protection by non peptidyl superoxide dismutase mimetic. Neuroscience letters, vol. 335(3); p. 163-166, ISSN: 0304-3940.
§ M. Iannone, C. Del Duca, T. Granato, V. Rispoli and G. Nisticò. Sound-evoked electrocortical desynchronization is inhibited by Nv-nitro-L-arginine methyl ester microinfused into the inferior colliculi in rats. 1996, Electroenceph. Clin. Neurophysiol. 99: 57-62.
§ M.C. Caroleo, V. Rispoli, M. Arbitrio, C. Strongoli, G. Rinaldi, D. Rotiroti & G. Nisticò. Chronic administration of paraquat produces immunosuppression of T lymphocytes and astrocytosis in rats. 1996, Toxic Substance Mechanism 15: 183-194.
§ G. Bagetta G., V. Rispoli, C. Del Duca, M. Iannone, T. Granato and G. Nisticò. Role of nitric oxide in the locus coeruleus in the maintenance of electrocortical arousal in rat. 1996, Pharmacol Com. Vol.7: 141-47.
§ Corasaniti MT, Rispoli V., Rotiroti D, Bagetta G. and Nistico G (1994). "Neurotoxicological profile of paraquat in the rat". in: Martignoni E., Nappi G. "Parkinson and other extrapiramidal disorders.". p. 23-31, London: Smoth-Gordon
§ V. Rispoli, R. Lopilato, E. Priolo, E. David, R. Marra and G. Nisticò. "Electrocortical desynchronization after microinfusion of kainic acid into the locus coeruleus in rats". 1994, Functional Neurology Vol IX (4): 203-208.
§ G. Bagetta, M. Iannone, I. Vecchio, V. Rispoli, D. Rotiroti and G. Nisticò. "Neurodegeneration produced by intrahippocampal injection of paraquat is reduced by sistemic administration of the 21-aminosteroid U74389F in rats". 1994, Free Rad. Res. 21, 85-93.
§ F. Abdulla, G. Dawe, A.M. Scorsa, V. Rispoli, J.D. Stephenson. "Effects of tetrahydro-9-aminoacridine on the electrocorticogram of rats with a unilateral lesion of the Nucleus Basalis Magnocellularis". 1992, Functional Neurology (7), 2: 141-144.
§ Stephenson J.D., Calaminici M.R., Rispoli V., Bagetta G. and Nisticò G. "Atropine-insensitive effects of 1,2,3,4-Tetrahydro-9-aminoacridine on behaviour and electrocortical activity of rats". 1991, Fundamental & Clinical Pharmacology Vol 5, No 5: 393.
§ Bagetta, G., De Sarro G., Sakurada S., Rispoli V., and Nisticò G. (1990). Different profile of electrocortical power spectrum changes after micro-infusion into the locus coeruleus of selective agonists at various opioid receptor subtypes in rats. British Journal of Pharmacology, vol. 101; p. 655-661, ISSN: 0007-1188.
§ M. Iannone, M. Calò, V. Rispoli and G. Nisticò." Behavioural, ECoG and neuropathological effects after intracerebral imection of MPP+ and paraquat in rats". 1989, Pharmacol. Res. 21 suppl.1: 43-4.
§ G.B. De Sarro, S. Sakurada, G. Bagetta, C. Ascioti, M.G. Audino, V. Rispoli and G. Nisticò. "Behavioural and ECoG spectrum power effects induced by microinfusion of compound acting at different opioid receptors into the locus coeruleus". 1988, Neurosciences Letters 33-S74.
§ M. Iannone, M. Calò, V. Rispoli, G. Sancesario and G. Nisticò. "Neuropathological lesions after microinfusion of paraquat and MPP+ into different areas of the rat brain". 1988, Acta Neurologica Vol. 10 (XLII) No 6: 313-21.